Project Summary We propose the Eating Disorders Genetics Initiative (EDGI) to rapidly and efficiently advance genomic discovery across the three major eating disorders (EDs) [AN (anorexia nervosa), BN (bulimia nervosa), and BED (binge-eating disorder)]. We propose a testable conceptualization of EDs as arising from a shared genetic vulnerability to a core trait (e.g., dysregulated appetite) that is further differentiated across clinical presentations of AN, BN, and/or BED by differing genetic predispositions to dimensional ED behaviors (e.g., binge eating, vomiting, excessive exercise), BMI, personality, comorbid psychopathology, physical activity, and metabolic traits. We propose that this palette of genetic risk is further influenced by environmental factors that affect emergence, course, and outcome of the ED. EDGI will empirically test and refine this model. Importantly, we will ascertain ancestrally diverse cases reflecting known epidemiological distributions of EDs. Using an efficient online ascertainment approach, EDGI will: (Aim 1) obtain deep phenotyping on course of illness, comorbid psychiatric conditions, treatment response, healthcare utilization, and quality of life on ~4000 participants in the Anorexia Nervosa Genetics Initiative (ANGI) from the US, Australia (AUS), and New Zealand (NZ); (Aim 2) ascertain, phenotype, and genotype 4500 new AN cases [(US, AUS, NZ, and Denmark (DK; identified in national records an genotypes from PKU cards from birth)]; ~5950 BN cases (US, AUS, NZ, DK); ~4050 BED cases (US, AUS, NZ) and 1500 controls; (Aim 3) conduct pre-planned genome-wide association studies (GWAS) for AN, BN, BED, any ED, and component behaviors, with external replications with Swedish and Icelandic data, plus a specific set of post-GWAS analyses; (Aim 4) apply advanced analytic strategies to test and refine our etiological model of EDs to explicate within-ED heterogeneity, explore the genetic relation between EDs and a broad array of psychiatric, metabolic, anthropometric, physical activity, educational phenotypes and the forces that shape those relationships, and preliminarily explore polygenic risk (PRS) x environmental interactions. EDGI represents the next logical step in ED genomics. Our scientific team recently completed ANGI, yielding compelling genetic findings for AN including the identification of 8 significant loci and intriguing genetic correlations with both psychiatric and metabolic traits strongly suggesting that AN is a metabo-psychiatric disorder. EDGI will expand to include BN and BED. Deliverables include: (a) rich phenotypic and genotypic data on large AN, BN, and BED samples; (b) clarification of the nature of genetic relationship among EDs and between EDs and other target traits; (c) an empirical model of ED risk and differentiation; (d) preliminary insight into how genes and environment interact in EDs; (e) sample and data deposit per current legal and regulatory standards and publicly available summary statistics. Our ultimate goal aligns with the Psychiatric Genomics Consortium (PGC) by delivering ?actionable? findings that will be transformable into biologically, clinically, and therapeutically meaningful insights on EDs.